This amended application proposes data analyses to model the potential effects of combination and structural interventions and their cost-effectiveness to optimize HIV prevention in Tijuana, Mexico. Since 2003, we have characterized dynamic, emerging sub-epidemics in Tijuana among people who inject drugs (PWID), female sex workers (FSWs), their clients and MSM. To guide policy makers and program planners, we will project the impact and cost-effectiveness of varying coverage of HIV interventions alone and in combination, to determine their optimal coverage for reducing HIV transmission to low levels. An innovative feature of our proposed work is to model `upstream' structural determinants associated with HIV infection in Tijuana (i.e., policing practices and entry into involuntary sex work). Our aims are: 1) To model overlapping HIV and syphilis epidemics occurring among different high risk groups in Tijuana (PWID, MSM, MSM-IDU, FSW, FSW-IDU, and their clients) to ascertain the extent to which HIV transmission is driven by specific risk groups and sexual or injecting risk behaviors. 2) To assess the impact and cost-effectiveness of scaling up coverage of existing and novel interventions (e.g. SEP, OST, ART, and two existing behavioral interventions), targeted at specific risk subgroups, to identify the most cost-effective combinatio intervention package to control HIV transmission. 3) To model the potential importance of policing practices and incarceration on HIV transmission among PWID in Tijuana, and the subsequent impact of a PEP on changing policing practices and HIV transmission. 4) To model the potential impact of reducing involuntary (i.e., forced/coerced) entry into sex trade as a minor or adult on HIV transmission in Tijuana. Our team of prevention scientists and modelers from the U.S., Mexico and the U.K. will utilize primary and secondary data from 8 NIH-funded R01s and related sub-studies in Tijuana. Mexican policy makers have also provided unprecedented access to program data. Given Tijuana's location as a corridor for drug and sex trafficking and its location on the Mexico-US border, Tijuana's HIV epidemic may represent what lies ahead for Mexico and Central America, and may significantly impact the U.S. HIV epidemic. Results will have policy and programmatic implications for Mexico and the U.S. Our project will advance efforts to model the potential impacts of structural determinants and combination prevention interventions on emerging HIV epidemics in lower and middle-income countries, and is responsive to the Office of AIDS Research's Trans-NIH Plan for 2015.